A Novel Role for IGF-1 Receptor in Growth Hormone Action

IGF-1 受体在生长激素作用中的新作用

• 批准号: 9178068
• 负责人: Stuart J Frank
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178068
• 关键词: Acute; Address; Alpha Cell; Area; Binding; Biological Assay; Bioluminescence; Cancer Biology; Cells; Chimera organism; Collaborations; Complement; Coupled; Coupling; Cytokine Receptors; Data; Dominant-Negative Mutation; Down-Regulation; Elements; Endocrine; Extracellular Domain; Extrahepatic; Functional disorder; Gene Expression; Genes; Growth; Growth Disorders; Growth Hormone Receptor; Hepatic; Hormone Responsive; In Vitro; Insulin Receptor; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Islet Cell; JAK2 gene; Knock-out; Knowledge; Liver; Luciferases; Mediating; Medicine; Metabolic; Metabolic Diseases; Metabolism; Methods; Modeling; Mus; Mutagenesis; Osteoblasts; Outcome; Pancreas; Pathway interactions; Phosphotransferases; Physiological; Physiology; Production; Protein Tyrosine Kinase; Proteins; Proteomics; Recombinants; Regulation; Reporting; Role; Signal Transduction; Somatomedins; Somatotropin; Stat5 protein; System; Testing; Therapeutic; Tissues; Work; base; cell type; glucose metabolism; hormone sensitivity; in vivo; member; metabolic phenotype; mutant; novel; novel strategies; novel therapeutics; prostate cancer cell; public health relevance; receptor; receptor binding; reconstitution; response

 DESCRIPTION (provided by applicant): Growth hormone (GH) regulates growth and metabolism by binding GH receptor (GHR), a cytokine receptor superfamily member, in target tissues. This activates the GHR-associated cytoplasmic tyrosine kinase, JAK2, and several signaling systems including STAT5. An important GH-induced outcome in some cell types is STAT5-mediated expression of the insulin-like growth factor (IGF)-1 gene and IGF-1 secretion. For six decades, our appreciation of GH physiology has been influenced by the somatomedin hypothesis, which held that GH-induced hepatically-derived circulating endocrine IGF-1 (aka somatomedin-C) mediates GH's somatogenic actions. Indeed, IGF-1 acts via the type 1 IGF-1 receptor (IGF-1R) to transmit tyrosine-kinase-mediated anabolic signals. However, our novel findings suggest IGF-1R also functions in relevant cell types (preadipocytes, islet -cells, osteoblasts, prostate cancer cells) as a proximal GHR-interacting element to augment GH sensitivity, even absent IGF-1 binding. Specifically, we find GH acutely promotes IGF-1R association with GHR and that IGF-1R deletion reduces acute GH signaling and consequent IGF-1 gene expression. IGF-1R reconstitution in IGF-1R-deleted cells rescues GH responsiveness in a fashion that depends on IGF-1R extracellular domain (ECD) elements. Further, a recombinantly-produced soluble IGF-1R ECD fragment containing these elements binds GHR in response to GH and blunts GH-induced signaling and gene expression in a dominant-negative fashion. Supporting our findings, recent reports indicate overlap in the metabolic phenotypes of mice with islet -cell-specific deletion of either GHR or IGF-1R, suggesting GHR-IGF-1R interaction is physiologically relevant in cell types that coexpress the receptors, unlike liver that is heavily endowed with GHR, but nearly devoid of IGF-1R. We hypothesize: 1) IGF-1R, by virtue of specific interaction with GHR, augments GH-induced somatogenic and metabolic signaling in a physiologically-relevant fashion. 2) Modulation of GHR-IGF-1R interaction could be a therapeutically-relevant target to promote or inhibit GH actions, particularly in non-hepatic tissues that express IGF-1R and when IGF-1R is aberrantly expressed in liver. Specific aims: 1) Define elements in IGF-1R that allow transmembrane-anchored IGF-1R to augment GH signaling; 2) Uncover specific modulators of GH action based on dominant-negative effects of soluble IGF-1R on GH signaling; 3) Examine functional effects of IGF-1R on GHR action in liver and pancreatic -cells in in vivo systems. Proposed studies address a fundamentally novel hypothesis about how GH-induced GHR action is influenced by physical and functional coupling of GHR with IGF-1R and IGF-1R-associated molecules. Our discoveries will enrich the "linear" GHGHRIGF-1IGF-1R pathway (somatomedin hypothesis), suggesting "parallel" GHR/IGF-1R-mediated effects, especially in extrahepatic GH action. Relationships of this work with aspects of metabolic regulation and other areas, including growth disorders and cancer biology, could be many and our results may suggest novel strategies to modulate GH action.

 描述(申请人提供)：生长激素(GH)通过结合目标组织中细胞因子受体超家族成员GH受体(GHR)来调节生长和代谢。这激活了GHR相关的细胞质酪氨酸激酶JAK2和包括STAT5在内的几个信号系统。在某些类型的细胞中，生长激素诱导的一个重要结果是STAT5介导的胰岛素样生长因子(IGF)-1基因的表达和IGF-1的分泌。60年来，我们对生长激素生理学的认识一直受到生长激素假说的影响，该假说认为生长激素诱导的肝源性循环内分泌IGF-1(又名生长激素-C)介导了生长激素的促体作用。事实上，IGF-1通过I型IGF-1受体(IGF-1R)传递酪氨酸激酶介导的合成代谢信号。然而，我们的新发现表明，胰岛素样生长因子-1R在相关的细胞类型(前脂肪细胞、胰岛-细胞、成骨细胞、前列腺癌细胞)中也作为生长激素受体的近端相互作用元件发挥作用，以增强生长激素敏感性，即使没有胰岛素样生长因子-1结合。具体地说，我们发现GH显著促进IGF-1R与GHR的关联，并且IGF-1R缺失减少了急性GH信号和随之而来的IGF-1基因表达。IGF-1R缺失细胞中的IGF-1R重组以一种依赖于IGF-1R胞外区(ECD)元件的方式拯救GH反应性。此外，重组产生的含有这些元件的可溶性IGF-1R ECD片段与GHR结合，以显性-负性方式钝化GH诱导的信号和基因表达。支持我们的发现的是，最近的报告表明，具有胰岛细胞特异性缺失的生长激素受体或胰岛素样生长因子-1R的小鼠的代谢表型存在重叠，这表明生长激素受体-胰岛素样生长因子-1R的相互作用在生理上与共同表达受体的细胞类型有关，不同于严重具有生长激素受体但几乎缺乏胰岛素样生长因子-1R的肝脏。我们假设：1)IGF-1R通过与GHR的特异性相互作用，以一种与生理相关的方式增强GH诱导的躯体发生和代谢信号。2)GHR-IGF-1R相互作用的调节可能是促进或抑制GH作用的治疗相关靶点，尤其是在表达IGF-1R的非肝组织和当IGF-1R在肝脏异常表达时。具体目标：1)确定胰岛素样生长因子-1R中允许跨膜锚定的胰岛素样生长因子-1R增强生长激素信号的元件；2)基于可溶性胰岛素样生长因子-1R对生长激素信号转导的显性-负性效应，揭示生长激素作用的特定调节器；3)在活体系统中检测胰岛素样生长因子-1R对肝脏和胰腺-细胞生长激素受体作用的功能影响。建议的研究提出了一个全新的假设，即GH诱导的GHR作用如何受到GHR与IGF-1R和IGF-1R相关分子的物理和功能耦合的影响。我们的发现将丰富“线性”的GHGHR胰岛素样生长因子-1-1R途径(生长激素假说)，提示“平行的”GHR/IGF-1R介导的作用，特别是在肝外的GH作用。这项工作与代谢调节和其他领域，包括生长障碍和癌症生物学的方面可能有许多关系，我们的结果可能建议新的策略来调节生长激素的作用。